Oral and Topical Treatment of Painful Diabetic Polyneuropathy: Practice Guideline Update Summary: Report of the AAN Guideline Subcommittee.

OBJECTIVE: To update the 2011 American Academy of Neurology (AAN) guideline on the treatment of painful diabetic neuropathy (PDN) with a focus on topical and oral medications and medical class effects. METHODS: The authors systematically searched the literature from January 2008 to April 2020 using a structured review process to classify the evidence and develop practice recommendations using the AAN 2017 Clinical Practice Guideline Process Manual. RESULTS: Gabapentinoids (standardized mean difference [SMD] 0.44; 95% confidence interval [CI], 0.21-0.67), serotonin-norepinephrine reuptake inhibitors (SNRIs) (SMD 0.47; 95% CI, 0.34-0.60), sodium channel blockers (SMD 0.56; 95% CI, 0.25-0.87), and SNRI/opioid dual mechanism agents (SMD 0.62; 95% CI, 0.38-0.86) all have comparable effect sizes just above or just below our cutoff for a medium effect size (SMD 0.5). Tricyclic antidepressants (TCAs) (SMD 0.95; 95% CI, 0.15-1.8) have a large effect size, but this result is tempered by a low confidence in the estimate. RECOMMENDATIONS SUMMARY: Clinicians should assess patients with diabetes for PDN (Level B) and those with PDN for concurrent mood and sleep disorders (Level B). In patients with PDN, clinicians should offer TCAs, SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (Level B) and consider factors other than efficacy (Level B). Clinicians should offer patients a trial of medication from a different effective class when they do not achieve meaningful improvement or experience significant adverse effects with the initial therapeutic class (Level B) and not use opioids for the treatment of PDN (Level B).

Efficacy and Safety of Efinaconazole 10% Solution in the Treatment of Onychomycosis in Diabetic Patients.

Onychomycosis is especially common among diabetic patients. The purpose of this study was to investigate the efficacy of 10% efinaconazole solution among diabetic subjects, without restriction by nail plate involvement or glycemic control. Forty subjects were enrolled, with 36 reaching their final 50-week follow-up visit. Mycological cure was attained by 21 subjects (58.33%); 8 subjects (20%) attained either clinical cure (0% clinical involvement) or treatment success (≤10% clinical involvement). Glycemic control did not affect clinical outcome. The medication was well tolerated, with 4 local adverse events and no significant adverse events. The medication may represent a useful option for diabetic patients.

Fourth-Year Podiatric Medical Student Perspectives on Clerkships and Residency Selection.

BACKGROUND: The fourth year of podiatric medical school is an important period in the education of the podiatric medical student, a period that consists largely of month-long clerkships. Nonetheless, there has been limited formal study of the quality of learning experiences during this period. Furthermore, there is limited knowledge of how podiatric medical students evaluate residency programs during clerkships. METHODS: An online survey was developed and distributed electronically to fourth-year podiatric medical school students. The focus of the survey was the quality of learning experiences during externships, and decision making in ranking residency programs. RESULTS: The most valuable learning experiences during clerkships were interactions with attending physicians, interactions with residents, and general feedback in surgery. Students self-identified that they most improved in the following areas during clerkships: forefoot surgery, clinical podiatry skills, and rearfoot surgery. The areas in which students improved the least were research, pediatrics, and practice management. The three most important factors students considered as they created their rank list were hands-on resident participation in surgical training, the attitude and personality of the residents, and the attitude and personality of the attending physicians. A range of surgical interest was identified among students, and students lacking in surgical interest self-reported less improvement in various surgical topics. CONCLUSIONS: The perspectives of fourth-year podiatric medical students are currently an underused resource. Improved understanding can help residency programs improve the quality of associated learning experiences and can make their programs more appealing to potential residency candidates.

Diabetes and cardiovascular disease in older adults: current status and future directions.

The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research.

Prevention: can we stop problems before they arise?

It is estimated that 50% of diabetic ulcerations and amputations can be prevented by identifying the at-risk foot and implementing preventative strategies. Patients with diabetes mellitus (DM) should be screened and placed in the appropriate risk category. Risk factors for the development of ulcer in several prospective studies include neuropathy, deformity, limited joint mobility, vascular disease, and history of previous ulceration or amputation. Early identification of the at-risk foot and placing the patient in the appropriate risk category is essential to prevention. Once the at-risk foot is identified, abnormal foot pressures should be reduced or eliminated using several treatment options. Repetitive, moderate mechanical stress (the pressure time integral) is often the initial mechanism of injury in the formation and/or recurrence of diabetic foot ulcers. Once conservative treatment options to off load the foot have failed, surgery should be considered. There are patients with diabetic foot ulcers for whom a combination of surgery (intrinsic off loading) and extrinsic off loading is better than either method alone. These difficult wounds are characterized by a combination of variables acting singularly or together, such as neuropathy, rigid deformity, limited joint mobility, and activity level. Our experience dictates, patients with rigid deformity and limited joint mobility get caught in the cycle of repetitive stress and cannot break the cycle until the etiology of the structural deformity is addressed surgically and preventative strategies for off loading, temperature monitoring, and activity level are implemented. If a structural deformity exists, the deformity will delay or prevent healing of the ulcer. Once the ulcer is healed, the likelihood for recurrence is high unless the deformity is corrected. When a structural deformity exists, the patient should be referred for evaluation and possible prophylactic surgery.

Toe and flow: essential components and structure of the amputation prevention team.

At the end of an anatomic peninsula, the foot in diabetes is prone to acute and chronic complications involving neuropathy, vasculopathy, and infection. Effective management requires an interdisciplinary effort focusing on this triad. In this article, we describe the key factors leading to foot complications and the critical skill sets required to assemble a team to care for them. Although specific attention is given to a conjoined model involving podiatry and vascular surgery, the "toe and flow" model, we further outline three separate models of care--basic, intermediate, and center of excellence--that can be implemented in the developed and developing world.

Toe and flow: essential components and structure of the amputation prevention team.

At the end of an anatomical peninsula, the foot in diabetes is prone to short- and long-term complications involving neuropathy, vasculopathy, and infection. Effective management requires an interdisciplinary effort focusing on this triad. Herein, we describe the key factors leading to foot complications and the critical skill sets required to assemble a team to care for them. Although specific attention is given to a conjoined model involving podiatric medicine and vascular surgery, the so-called toe and flow model, we further outline three separate programmatic models of care--basic, intermediate, and center of excellence--that can be implemented in the developed and developing world.

Cryosurgery for the treatment of heel pain.

BACKGROUND: Although cryosurgery has been used to treat certain conditions, its efficacy for the treatment of heel pain has not been established. The objective of this retrospective case series was to investigate both short- and long-term changes in heel pain after cryosurgery. MATERIALS AND METHODS: A sample of 137 feet (n = 137) was analyzed over a 24-month period after cryosurgery. The mean age was 56 years and the mean BMI was 33. Subjects in our analysis included only those who had failed 6 months of conservative care prior to cryosurgery. Pain was measured using a Numeric Pain Scale (NPS, zero to 10) at 3 weeks and 24 months. Statistics were calculated using SPSS version 12.0 (Chicago, IL). RESULTS: A total of 106 subjects had successful pain relief and 31 subjects failed to gain relief; the success and failure rates were 77.4% and 22.6%, respectively. Mean pain before cryosurgery was 7.6, after cryosurgery at three weeks was 1.6 (p < 0.0005), and after cryosurgery at 24 months was 1.1 (p < 0.0005). CONCLUSION: In subjects who achieved successful pain relief, the significantly lower mean pain score at 3 weeks and 24 months, compared to the initial pain score prior to cryosurgery, suggests that cryosurgery was successful in resolving both short- and long-term heel pain.

Mortality of first-time amputees in diabetics: a 10-year observation.

AIMS: We analyze mortality of first-time diabetic amputees by stratifying by level of amputation, differentiating short-term and long-term mortality. METHODS: We evaluated 277 diabetic patients who received their first lower extremity amputation (LEA) during 1993-97. Subjects were followed until December 2003, and categorized by level of amputation. We compared the mortality difference by level for 0-10 years, 0-10 months, and 10 months-10 years, and examined the association of comorbid conditions and death for each level. RESULTS: We found a significant difference in mortality by amputation level for 0-10 years (p<0.05) and <10 months (p<0.01) survival, but not for the one of 10 months-10 years. For major amputees deceased within 10 months, sepsis was as frequent a cause of death as cardiovascular disease. In distal amputees, CVD, CAD and ESRD were strongly associated with death, but only CAD was associated death among major amputees. CONCLUSION: For diabetic patients undergoing first LEAs, the mortality of major amputees was worse than that of minor amputees due to the difference in first 10-month mortality. The history of comorbid conditions in first-time major amputees was less important than in minor amputees since sepsis was the frequent cause of death in major amputees in this early period.

Levels of endothelial nitric oxide synthase and calcitonin gene-related peptide in the Charcot foot: a pilot study.

UNLABELLED: The pathogenesis of Charcot neuroarthropathy is unclear. To investigate the possibility that decreased levels of calcitonin gene-related peptide and endothelial nitric oxide synthase are involved in the process, we studied bone samples from healthy subjects (n = 4), subjects with diabetic neuropathy (n = 4), and subjects with Charcot neuroarthropathy (n = 4). A statistically significant difference was found in endothelial nitric oxide synthase expression between bone specimens in patients with diabetic neuropathy, Charcot neuroarthropathy, and normal bone (P = .008). A trend toward calcitonin gene-related peptide intensification was observed in normal bone as compared to diabetic neuropathy and Charcot neuroarthropathy bone specimens, but it did not reached statistical significance (P = .23). This pilot study suggests that abnormal calcitonin gene-related peptide and endothelial nitric oxide synthase activity may play a role in the development of Charcot neuroarthropathy. LEVEL OF CLINICAL EVIDENCE: 4.

Fibronectin fragmentation is a feature of periodontal disease sites and diabetic foot and leg wounds and modifies cell behavior.

BACKGROUND: Fibronectin (FN) undergoes fragmentation in periodontal disease sites and in poorly healing diabetic wounds. The biologic effects of FN fragments on wound healing remain unresolved. This study characterized the pattern of FN fragmentation and its effects on cellular behavior compared to intact FN. METHODS: Polyclonal antibodies were raised against FN and three defined recombinant segments of FN and used to analyze gingival crevicular fluid from periodontal disease sites in systemically healthy subjects and in subjects with diabetes, as well as chronic leg and foot wound exudates from subjects with diabetes. Subsequently, the behavior of human gingival fibroblasts (hGFs) and HT1080 reference cells were analyzed by measuring cell attachment, migration, and chemotaxis in the presence of intact FN or recombinant FN fragments. RESULTS: FN fragmentation was evident in fluids from periodontal disease sites and diabetic leg and foot wounds. However, no fragmentation pattern distinguished systemically healthy subjects from subjects with diabetes. hGFs and HT1080 cells required significantly higher concentrations of FN fragments to achieve attachment comparable to intact FN. Cells cultured on FN fragments also were morphologically different from cells cultured on full-length FN. Migration was reduced for hGFs cultured on FN fragments relative to full-length FN. In contrast, FN fragments increased HT1080 fibrosarcoma cell migration over intact FN. CONCLUSIONS: FN fragmentation is a prominent feature of periodontal and chronic leg and foot wounds in diabetes. Furthermore, cell culture assays confirmed the hypothesis that exposure to defined FN fragments significantly alters cell behavior.

Lateral plantar artery aneurysm: a case report.

We report a case of a true plantar artery aneurysm in an adult. True aneurysms of the inframalleolar vessels are rare. The limited literature on the subject is reviewed, including differential diagnosis and suggested treatment.

Ciclopirox 8% nail lacquer topical solution for the treatment of onychomycosis in patients with diabetes: a multicenter, open-label study.

BACKGROUND: An open-label, noncomparative study was conducted to assess the safety and efficacy of ciclopirox 8% nail lacquer topical solution in patients with type 2 diabetes mellitus. METHODS: Forty-nine diabetic patients with distal subungual onychomycosis were treated once daily for 48 weeks with ciclopirox 8% nail lacquer, a topical nail solution approved for the treatment of patients with mild-to-moderate onychomycosis. RESULTS: Treatment resulted in clinical improvement in 63.4% of patients. Most patients (85.7%) had a mycologic outcome of improvement or cure, with 54.3% attaining mycologic cure. Consideration of mycologic and clinical outcomes generated a treatment outcome of improvement, success, or cure in 84.4% of patients. Moreover, patients experienced improvement in the diseased area of the nail (63.4%), nail surface (56.1%), nail color (48.8%), and nail thickness (65.9%). Ciclopirox 8% nail lacquer was safe, with treatment-related adverse events limited to infection in one patient, which resolved in 15 days; the patient completed the study. No treatment-related serious adverse events were observed. CONCLUSION: Ciclopirox 8% nail lacquer is a safe and effective treatment for distal subungual onychomycosis in patients with type 2 diabetes mellitus receiving insulin or oral hypoglycemic therapy.

Toenail assessment tool for quantitation of visibly infected mycotic nail plate in onychomycosis.

Typically, the amount of mycotic nail involvement in onychomycosis (fungal infection of the nail) before and after drug therapy is determined visually. Because there is an inherent element of subjectivity, it is difficult to accurately measure and compare results across clinical trials or to assess how much improvement has been achieved in response to therapy. We developed a simple tool for measuring mycotic nail involvement. This novel tool consists of a large grid containing 5 toenail templates of varying nail morphologies that are derived from the actual shape of the toenail of the great toe in several males and females, and one standardized computer-generated nail shape. The toenail templates are presented in 7 different sizes to match different nail sizes. Each toenail template is further divided into 8 segments, each comprising approximately 12.5% of the total nail surface. Measurement of the percentage of mycotic nail involvement is accomplished by the following procedure: (1) placing tracing film over the target toenail; (2) tracing the outline of the entire toenail, followed by tracing the affected portion of the toenail on the same film; (3) placing the tracing film over a nail template on the grid that best fits the shape of the toenail; and (4) counting the number of grid segments that correspond to 50% or more involvement. To assess feasibility, the tool was used in a large randomized trial involving over 30 sites and 500 subjects with onychomycosis. This tool is a more accurate and less biased alternative to visual assessment for measuring nail involvement or progression of nail clearing.

Treatment of toenail onychomycosis with oral terbinafine plus aggressive debridement: IRON-CLAD, a large, randomized, open-label, multicenter trial.

This study was conducted to investigate the efficacy of oral terbinafine with and without aggressive debridement for the treatment of toenail onychomycosis. Onychomycosis patients aged 18 to 75 years received 12 weeks of terbinafine, 250 mg/day, alone (n = 255) or with aggressive debridement (n = 249). Both groups showed marked improvement from baseline at all time points. At week 48, complete, mycologic, and clinical cure rates were higher in the terbinafine plus debridement group compared with the terbinafine alone group, although significance was reached only for clinical cure (59.8% versus 51.4%; P = .023). Although approximately 39% of the patients received at least one antidiabetic, antihypertensive, or cholesterol-lowering agent concomitantly, including statins, the incidence of treatment-emergent adverse events was low and the adverse events were generally mild to moderate in severity. No clinically significant changes in liver transaminase levels were observed 6 weeks after treatment or after 12 weeks in those tested. These results support the well-established safety and efficacy of terbinafine for treatment of onychomycosis.

Current concepts in diabetic microvascular dysfunction.

Microvascular dysfunction is an important component of the pathologic processes that occur in diabetic foot disease. The endothelial abnormalities observed in patients with diabetes mellitus are poorly understood, and evidence suggests that endothelial dysfunction could be involved in the pathogenesis of diabetic macroangiopathy and microangiopathy. With the advent of insulin replacement in the early 1900s and increased efforts toward metabolic control of diabetes, long-term complications of this disease have become apparent. These late-term complications are primarily disorders of the vascular system. This article reviews the process of microvascular dysfunction and how it may relate to the pathogenesis of diabetic foot problems.

Risk of reamputation in diabetic patients stratified by limb and level of amputation: a 10-year observation.

OBJECTIVE: This study examined the risk of reamputation, stratified by original level of amputation, in a population of diabetic patients. We also illustrated reamputation rates by ipsilateral and contralateral limbs. RESEARCH DESIGN AND METHODS: The study population included 277 diabetic patients with a first lower-extremity amputation performed between 1993 and 1997 at University Hospital in San Antonio, Texas. Reamputation episodes for the ipsilateral and contralateral limbs were recorded through 2003. Using a cumulative incidence curve analysis, we compared the reamputation rate by limb. Cumulative rates of reamputation were calculated for each limb at each amputation level at 1, 3, and 5 years. RESULTS: Cumulative rates of reamputation per person were 26.7% at 1 year, 48.3% at 3 years, and 60.7% at 5 years. Ipsilateral reamputation per amputation level at the 1-, 3-, and 5-year points were toe: 22.8, 39.6, and 52.3%; ray: 28.7, 41.2, and 50%; midfoot: 18.8, 33.3, and 42.9%; and major: 4.7, 11.8, and 13.3%. For contralateral reamputation, the rates at 1, 3, and 5 years were toe: 3.5, 18.8, and 29.5%; ray: 9.3, 21.6, and 29.2%; midfoot: 9.4, 18.5, and 33.3%; and major: 11.6, 44.1, and 53.3%. CONCLUSIONS: This study showed that a patient is at greatest risk for further same-limb amputation in the 6 months after the initial amputation. Although risk to the contralateral limb rises steadily, it never meets the level of that of the ipsilateral limb. This finding will help clinicians focus preventive efforts and medical resources during individualized at-risk periods for diabetic patients undergoing first-time amputations.

Improved foot sensitivity and pain reduction in patients with peripheral neuropathy after treatment with monochromatic infrared photo energy--MIRE.

The medical records of 2239 patients (mean age=73 years) with established peripheral neuropathy (PN) were examined to determine whether treatment with MIRE was, in fact, associated with increased foot sensitivity to the Semmes Weinstein monofilament (SWM) 5.07 and a reduction in neuropathic pain. The PN in 1395 of these patients (62%) was due to diabetes. Prior to treatment with MIRE, of the 10 tested sites (5 on each foot), 7.1+/-2.9 were insensitive to the SWM 5.07, and 2078 patients (93%) exhibited loss of protective sensation defined by Medicare as a loss of sensation at two or more sites on either foot. After treatment, the number of insensate sites on both feet decreased to 2.4+/-2.6, an improvement of 66%. Of the 2078 (93%) patients initially presenting with loss of protective sensation, 1106 (53%) no longer had loss of protective sensation after treatment (P<.0001); 1563 patients (70%) also exhibited neuropathic pain in addition to sensory impairment. Prior to treatment with MIRE, pain measured on the 11-point visual analogue scale (VAS) was 7.2+/-2.2 points, despite the use of a variety of pain-relieving therapeutic agents. After treatment with MIRE, pain was reduced by 4.8+/-2.4 points, a 67% reduction. Therefore, MIRE appears to be associated with significant clinical improvement in foot sensation and, simultaneously, a reduction in neuropathic pain in a large cohort of primarily Medicare aged, community-dwelling patients, initially diagnosed with PN. The quality of life associated with these two outcomes cannot be underappreciated.